The intractable process of
fibrosis underlies the pathogenesis of
systemic sclerosis (SSc) and other diseases, and in aggregate contributes to 45% of deaths worldwide. Because currently there is no effective anti-fibrotic
therapy, a better understanding of the pathways and cellular differentiation programs underlying
fibrosis are needed. Emerging evidence points to a fundamental role of the
nuclear hormone receptor peroxisome proliferator activated receptor-γ (
PPAR-γ) in modulating fibrogenesis. While
PPAR-γ has long been known to be important in lipid metabolism and in
glucose homeostasis, its role in regulating mesenchymal cell biology and its association with pathological
fibrosis had not been appreciated until recently. This article highlights recent studies revealing a consistent association of
fibrosis with aberrant
PPAR-γ expression and activity in various forms of human
fibrosis and in rodent models, and reviews studies linking genetic manipulation of the
PPAR-γ pathway in rodents and
fibrosis. We survey the broad range of anti-fibrotic activities associated with
PPAR-γ and the underlying mechanisms. We also summarize the emerging data linking
PPAR-γ dysfunction and
pulmonary arterial hypertension (PAH), which together with
fibrosis is responsible for the mortality in patients in SSc. Finally, we consider current and potential future strategies for targeting
PPAR-γ activity or expression as a
therapy for controlling
fibrosis.